Substituted imidazoles useful in the treatment of inflammatory disease

• US 5,965,583 A
• Filed: 04/17/1998
• Issued: 10/12/1999
• Est. Priority Date: 04/24/1997
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Beers, Scott A., Wu, Wei, Wachter, Michael P., Malloy, Elizabeth A.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US09/062,304
• Time in Patent Office: 543 Days
• Field of Search: 546/274.1, 514/341
• US Class Current: 514/341
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 7/0812 comprising a heterocyclic ring

Abstract

This invention relates to a series of substituted imidazoles of Formula I ##STR1## pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, and are useful in the treatment of diseases associated with overproduction of inflammatory cytokines.

Claims

1. A compound of Formula I ##STR37## wherein:

R₁ is phenyl, substituted phenyl where the substituents are selected from the group consisting of C_1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile, or pyridinyl;

R₂ is phenyl, substituted phenyl where the substituents are selected from the group consisting of C_1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile or pyridinyl where the pyridinyl is optionally C_1-4 alkyl substituted;

R₃ is hydrogen, SEM, C_1-5 alkoxycarbonyl, aryloxycarbonyl, arylC_1-5 -alkyloxycarbonyl, arylC_1-5 alkyl, substituted arylC_1-5 alkyl where the aryl substituents are independently selected from one or more members of the group consisting of C_1-5 alkyl, C_1-5 alkoxy, halogen, amino, C_1-5 alkylamino, and diC_1-5 alkylamino, phthalimidoC_1-5 -alkyl, aminoC_1-5 alkyl, diaminoC_1-5 alkyl, succinimidoC_1-5 alkyl, C_1-5 alkylcarbonyl, arylcarbonyl, C_1-5 alkylcarbonylC_1-5 alkyl, aryloxycarbonylC_1-5 alkyl;

R₄ is (A)--(CH₂)_q --X where;

A is vinylene, ethynylene or ##STR38## where R₅ is selected from the group consisting of hydrogen, C_1-5 alkyl, phenyl and phenylC_1-5 alkyl;

q is 0-9;

X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine), ethynyl, substituted ethynyl (where the substituents are selected from one or more of the group consisting of fluorine, bromine chlorine and iodine, C_1-5 alkyl, substituted C_1-5 alkyl where the alkyl substituents are selected from the group consisting of one or more C_1-5 alkoxy trihaloalkyl, phthalimido and amino, C_3-7 cycloalkyl, C_1-5 alkoxy, substituted C_1-5 alkoxy where the alkyl substituents are selected from the group consisting of phthalimido and amino, phthalimidooxy, phenoxy, substituted phenoxy (where the phenyl substituents are selected from the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy), phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy, arylC_1-5 alkyl, substituted arylC_1-5 alkyl where the aryl substituents are selected from the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy, arylhydroxyC_1-5 alkyl amino, C_1-5 alkylamino, diC_1-5 alkylamino, nitrile, oxime, benxyloxyimino, C_1-5 alkyloxyimino, phthalimido, succinimido, C_1-5 alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy where the phenyl substitutents are selected from the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy, phenylC_1-5 alkylcarbonyloxy, where the phenyl substitutents are selected from the group consisting of C_1-5 alkyl, halogen and C_1-5 alkoxy, aminocarbonyloxy, C_1-5 alkylaminocarbonyloxy, diC_1-5 alkylaminocarbonyloxy, C_1-5 alkoxycarbonyloxy, substituted C_1-5 alkoxycarbonyloxy where the alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl and hexyl, phenoxycarbonyloxy, substituted phenoxycarbonyloxy where the phenyl substituents are selected from the group consisting of C_1-5 alkyl, C_1-5 alkoxy, and halogen, C_1-5 alkylthio, substituted C_1-5 alkylthio where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C_1-5 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are selected from the group consisting of bromine, fluorine, chloride, C_1-5 alkoxy and trifluoromethyl;

with the proviso;

if A is ##STR39## q is 0 and X is H, R₃ may not be SEM; and

pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where R₁ is substituted phenyl and R₂ is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

3. The compound of claim 2 where R₁ is 4-fluorophenyl and R₂ is pyridin-4-yl.

4. The compound of claim 3 where R₃ is hydrogen, arylC_1-5 alkyl, or substituted arylC_1-5 alkyl.

5. The compound of claim 4 where R₃ is hydrogen or phenylC_1-5 alkyl.

6. The compound of claim 5 where A is ethynylene and q is 0-5.

7. The compound of claim 6 where X is succinimido, hydroxy, methyl, phenyl, C_1-5 alkylsulfonyl, C_3-6 -cycloalkyl, C_1-5 alkylcarbonyloxy, C_1-5 alkoxy, phenylcarbonyloxy, C_1-5 alkylamino, diC_1-5 alkylamino, or nitrile.

12. The compound of claim 1 where R₁ is phenyl and R₂ is selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

13. The compound of claim 12 where R₂ is pyridin-3-yl.

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier or diluent.

8. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-hydroxypropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(6-hydroxyhexyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.

16. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier or diluent.

9. A compound 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole and pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier or diluent.

10. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(5-cyanopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-dimethylaminobutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-(phenylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-methylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-cyclopentylpropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-(butylsulfonyl)pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.

11. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(octyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-butylthiopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-phenylpentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(5-chloropentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phthalimidolpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-N-succinimidopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.